Thromboembolic disorders and hypertension in women have been strongly correlated with oral contraceptive use. Alterations in the renin-angiotensin and hematologic systems include shortening of Thrombotest time and increase in factor VII and plasma renin activities in cold-stored plasmas. Recently, we demonstrated high Hageman factor (HF) titers in oral contraceptive (OCA) users and correlated this observation with the cold-activation of factor VII (CPA). This grant request aims to investigate the mechanisms involved in CPA, HF snythesis and activation. These include the following objectives: 1) to determine whether activated HF is present in the plasma of OCA users, 125I-anti-HF will be added to normal and OCA user's plasmas upon reduction with beta-mercaptoethanol and SDS-agarose electrophoresis; 2) to determine whether fragmentation of HF occurs with cooling in OCA user's plasma, 125I-HF will be added to normal, Hageman trait and OCA user's plasmas and then subjected to SDS polyacrylamide electrophoresis, before and 20 hours after cold storage; 3) to determine whether a high HF titer is needed to increase kallikrein formation in cold-stored plasma, kallikrein generation will be measured in normal, prekallikrein-deficient and OCA user's plasmas and in HF-fortified normal plasma, before and after cold storage; 4) to determine whether surface-mediated clotting factors other than HF are needed for CPA, factor VII activity and prothrombin time will be measured in mixtures of purified HF and plasmas deficient in prejallikrein, high molecular weight kininogen or plasma thromboplastin antecedent before and after cold storage; 5) to determine whether high HF titer is needed to increase plasma renin activity in cold-stored plasma, plasma renin activity will be measured in normal, Hageman trait and HF-fortified normal plasma before and after cold storage; 6) to determine whether the estrogen component in OCAs is responsible for the high HF titer among OCA users, estradiol benzoate will be injected into ovariectomized rats for one to two weeks during which serial HF clot-promoting assays will be performed. Rat liver perfusion studies will also be performed to compare de novo HF synthesis in estrogen treated and non-treated groups. These experiments aim to explore the possible role of elevated titer of HF in thrombosis and hypertension observed in OCA users.